Antimicrobials and the emergence of disease-specific therapies
Sir Alexander Fleming’s discovery of the anti-microbial activity of
penicillin in 1928 is often considered the first disease-specific
therapy (5). In actual fact, this seminal observation did not translate
into changes in care until well after the widespread use of another
antimicrobial drug, sulfanilamide. The scientific community initially
responded with little enthusiasm for “mould juice”, and given
challenges associated with producing the antimicrobial in large
quantities, Fleming had initially considered penicillin to be most
useful as a potential surface cleaner or as an agent to help isolate
bacteria in culture (6). At the same time, in the early 1930s, Dr.
Gerhard Domagk, a German physician, was exploring the use of various
chemical agents to combat bacterial infections. In this work, he found
that the sulphonamide groups in azo dyes offered potential as
antimicrobial agents, notably the compound Prontosil™. Famously, the
first human to benefit from his landmark advance was his own daughter.
When six year old Hildegard developed a serious Strep infection,
and amputation of her arm was being considered, he treated her with
Prontosil™ and she quickly recovered,.. In 1935, he published his work
demonstrating that mice infected with Streptococci survived when
administered a single dose of a synthetic azo dye (7). His work led to
the introduction of Prontosil™ to the market shortly thereafter.
Tréfouël and Tréfouël and colleagues at the Pasteur Institute
subsequently determined that the active agent in Prontosil™ was the
sulphonamide sulfanilamide (8).
The impact of the introduction of specific and effective medical therapy
on health care –specifically child health care - and medical culture
was substantial and permanent. As described by Lewis Thomas, the role of
the physician up to the early 20th Century had been
primarily to provide supportive care to suffering patients, including
providing explanations to support diagnosis and suggest outcome, with
cure being reserved (in certain and limited cases) to surgeons (9).
Prior to the 1940’s, for most patients with infection, medical
management includes watchful waiting and symptom management until the
infection resolved or the patient succumbed. The establishment of
effective antimicrobial therapy was a paradigm-changing event,
comparable today to curing all cancer, or reversing now-irreversible
neurologic injury (9). As effective antimicrobial therapy became
available, the mortality rate from meningitis fell from 95% to 5%.
Similarly, death from pneumonia or bacterial skin infection –
previously common – became rare. In parallel, the pharmaceutical
industry formalized itself, and came to recognize the significant
potential associated with disease-specific cures, which launched a
focused search for other new molecular entities (1,5). The Therapeutic
Revolution that followed these fundamental discoveries first led to a
wave of new treatments based on innovative small molecules and
subsequently led to the revolution in biological and gene-based
therapies.
For children, this focus on disease-specific therapy has been profound
for some disorders. While the first and arguably largest impact was with
infectious diseases, advances in the understanding of the fundamentals
of paediatric drug therapy, including paediatric pharmacokinetics and
the role of therapeutic drug monitoring – led to substantial changes in
the management of other common and serious disorders in childhood.
Childhood cancer, which had a nearly universally fatal outcome less than
a century ago, now boasts cure rates, for some of the commonest cancers,
of 80 to 90% in large part due to highly effective therapy (10).
Paediatricians and other child health care providers have proven adroit
at applying medications developed for adult indications into paediatric
practice, often very shortly after the drug in question entered the
market.